Robust increases in nonrapid-eye movement sleep (NREMS) occur in response to sleep deprivation, infection, and mild increases in ambient temperature (Tamb). We hypothesize that interleukin-1Beta(IL-1Beta) mediates NREMS responses to sleep deprivation, infection, and Tamb. The IL-1 family includes 3 structurally related proteins IL-1alpha, IL-1Beta, and the IL-1 receptor antagonist (IL-1ra), and the type I and II-IL-1 receptors. Much data implicates IL-1Beta in NREMS regulation, e.g., exogenous IL-1Beta enhances NREMS in several species. Preliminary data also support the hypothesis, e.g., NREMS rebound after sleep deprivation is attenuated if animals are pretreated with anti-IL-1Beta or the IL-1ra. Four specific aims (SAs) are proposed to further test the hypothesis. Four blockers of the family of IL-1 molecules, each having a unique action, will be used in combination with sleep deprivation (SA #1), injection of somnogenic microbial products (SA#2), and mild increased in Tamb (SA#3). The blockers are anti-IL-1alpha, anti-IL-1Beta, the IL-1ra, and a soluble IL-1 type I receptor. In these experiments, it will be determined whether central or systemic changes in the IL-1 family are relevant to NRMES responses in rabbits. In separate concurrent experiments (SA#4) we will determine levels of IL-1alpha, IL-1Beta and the IL-1ra in blood and specific brain regions after sleep deprivation, injection of microbial products, and mild increases in Tamb. It is predicted that regardless of the method used to increase sleep propensity, CNS IL-1Beta will increase. If increased IL-1Beta is blocked, NREMDS response will also be blocked. Further, we predict that the IL-1ra will also increase in brain with a delay relative to IL-1Beta. Expected data will have bearing on whether the IL-1 family serves a physiological role in sleep regulation. Sleep remains an enigma; we know neither its functions nor the exact cellular and molecular mechanisms responsible for sleep. Knowledge of the molecular causes of sleep is likely to be a necessary step toward our understanding of sleep function; expected results will greatly aid this endeavor.